Amide compounds and use of the same

Abstract

An amide compound of the formula (I):   wherein R is amino and the like, A is alkylene and the like, X is O, S and the like, M is arylene and the like, R 1 , R 2 , R 3 and R 4 are H, hydroxy and the like, R 5 is H, alkyl and the like, m is an integer of 0-6, R 6 is an optionally substituted aryl and the like, and R 7 is H, an optionally substituted alkyl and the like, a pharmaceutically acceptable acid addition salt thereof and a pharmaceutical containing same as an active ingredient. The amide compounds exhibit superior suppressive effects on cytokines directly or indirectly involved in inflammations, such as IL-8, IL-1, IL-6, TNF-α, GM-CSF and the like, and are useful for the prophylaxis and treatment of rheumatic diseases, arthritis due to gout and the like.

1. An amide compound of the formula (I): 
       
         
           
           
               
               
           
         
       
         
       wherein:
 R is a piperazinyl optionally substituted by lower alkyl, a piperidyl optionally substituted by lower alkyl or an amino 
 wherein amino is optionally substituted by lower alkyl;  
 
 A is a linear alkylene;  
 X is an oxygen atom, a sulfur atom, —NH—or—CH 2 —;  
 M is an arylene;  
 R 1 , R 2 , R 3  and R 4  are the same or different and each is a hydrogen atom, provided at least one of R′, R 1 , R 2 , R 3  and R 4  is not a hydrogen atom, a hydroxy, a halogen atom, or —O—CO—R 11 ″′ wherein R 11 ″′ is lower alkyl optionally substituted by a substituent selected from the group consisting of amino, acyloxy and benzyloxycarbonyl, or phenyl optionally substituted by lower alkyl;  
 R 5  is hydrogen atom;  
 m is 1;  
 R 6  is a phenyl and  
 R 7  is —COO—R 12″  
 wherein R 12 ″′ is hydrogen atom, aralkyl, adamantyl, cyclohexylideneamino,  
 cyclohexyl optionally substituted by lower alkyl, piperidyl optionally substituted by lower alkyl, or alkyl optionally substituted by a substituent selected from the group consisting of hydroxy, lower alkoxy, lower alkoxy lower alkoxy, lower alkoxycarbonyl, acyloxy, piperazinyl and amino optionally substituted by lower alkyl;  
 or a pharmaceutically acceptable acid addition salt thereof.  
 
 
     
     
       2. The amide compound of  claim 1 , wherein H M is phenylene, or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       3. The amide compound of  claim 1 , wherein R 7  is —COO—R 12 ″″ wherein R 12 ″″ is lower alkyl, or cyclohexyl which is optionally substituted by lower alkyl, or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       4. The amide compound of  claim 1 , wherein X is an oxygen atom or —CH 2 —, or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       5. The amide compound of  claim 1 , wherein R 6  is phenyl and m is 1, or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       6. The amide compound of  claim 1 , wherein R 1 , R 2 , R 3  and R 4  are the same or different and each is a hydrogen atom provided that at least one of R 1 , R 2 , R 3  and R 4  is not a hydrogen atom, hydroxy, a halogen atom, or —O—CO—R 11 ″″ wherein R 11 ″″ is lower alkyl or phenyl, or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier; and the amide compound of any one of  claims 1  to  6  or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       8. A method for suppressing the production of cytokines, comprising administering to a patient in need thereof, an inflammatory cytokine production suppressor comprising an amide compound of any one of  claims 1  to  6  or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 
     
     
       9. A method for treating or prophylaxis of inflammatory diseases, comprising administering to a patient in need thereof, an agent for treating or prophylaxis of inflammatory diseases comprising an amide compound of any one of  claims 1  to  6  or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 
     
     
       10. An amide compound of formula: 
       
         
           
           
               
               
           
         
       
         
       
         or a pharmaceutically acceptable acid addition salt thereof. 
       
     
     
       11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the amide compound of  claim 10  or a pharmaceutically acceptabe acid addition salt thereof. 
     
     
       12. A method of suppressing the production of cytokines, comprising administering to a patient in a need thereof, an inflammatory cytokine production suppressor comprising the amide compound of  claim 10  or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 
     
     
       13. A method for treating or prophylaxis of inflammatory diseases, comprising administering to a patient in need thereof, an agent for treating or prophylaxis of inflammatory diseases comprising the amide compound of  claim 10  or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 
     
     
       14. An amide compound of the formula: 
       
         
           
           
               
               
           
         
       
         
       
        
       
     
     
       15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the amide compound of  claim 14 . 
     
     
       16. A method of suppressing the production of cytokines, comprising administering to a patient in need thereof, an inflammatory cytokine production suppressor comprising the amide compound of  claim 14 . 
     
     
       17. A method for treating or prophylaxis of inflammatory diseases, comprising administering to a patient in need thereof, an agent for treating or prophylaxis of inflammatory diseases comprising the amide compound of  claim 14 .